SMART: PI3K_rbd domain annotation

PI3K_rbd PI3-kinase family, Ras-binding domain

SMART accession number:	SM00144
Description:	Certain members of the PI3K family possess Ras-binding domains in their N-termini. These regions show some similarity (although not highly significant similarity) to Ras-binding RA domains (unpublished observation).
Interpro abstract (IPR000341):	Phosphatidylinositol 3-kinases (PI3Ks) are lipid kinases that phosphorylate 4,5-bisphonate (PI(4,5) P2 or PIP2) at the 3-position of the inositol ring, and thus generate phosphatidylinositol 3,4,5-trisphosphate (PIP3), which, in turns, initiates a vast array of signaling events. PI3Ks can be grouped into three classes based on their domain organisation. Class I PI3Ks are heterodimers consisting of a p110 catalytic subunit and a regulatory subunit of either the p85 type (associated with the class IA p110 isoforms p110alpha, p110beta or p110delta) or the p101 type (associated with the class IB p110 isoform p110gamma). Common to all catalytic subunits are an N-terminal adaptor-binding domain (ABD) that binds to p85, a Ras- binding domain (RBD), a putative membrane-binding domain (C2), a helical domain of unknown function, and a kinase catalytic domain. Class II PI3Ks lack the ABD domain and are distinguished by a carboxy terminal C2 domain. Class III enzymes lack the ABD and RBD domains [ (PUBMED:17626883) (PUBMED:18079394) (PUBMED:20081827) (PUBMED:10580505) ]. PI3K RBD is a small globular domain of about 100 residues in length with an alpha/beta-sandwich topology. The PI3K RBD domain consists of a five-stranded mixed beta-sheet flanked by two alpha-helices [ (PUBMED:17626883) (PUBMED:18079394) (PUBMED:20081827) (PUBMED:10580505) ].
Family alignment:	View or

There are 3332 PI3K_rbd domains in 3329 proteins in SMART's nrdb database.

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Evolution (species in which this domain is found)
Taxonomic distribution of proteins containing PI3K_rbd domain.
This tree includes only several representative species. The complete taxonomic breakdown of all proteins with PI3K_rbd domain is also avaliable.

Click on the protein counts, or double click on taxonomic names to display all proteins containing PI3K_rbd domain in the selected taxonomic class.
Cellular role (predicted cellular role)
Binding / catalysis: protein-binding, Ras-binding
Literature (relevant references for this domain)
Primary literature is listed below; Automatically-derived, secondary literature is also avaliable.
- Walker EH, Perisic O, Ried C, Stephens L, Williams RL
- Structural insights into phosphoinositide 3-kinase catalysis and signalling.
- Nature. 1999; 402: 313-20
- Display abstract
- Phosphoinositide 3-kinases (PI3Ks) are ubiquitous lipid kinases that function both as signal transducers downstream of cell-surface receptors and in constitutive intracellular membrane and protein trafficking pathways. All PI3Ks are dual-specificity enzymes with a lipid kinase activity which phosphorylates phosphoinositides at the 3-hydroxyl, and a protein kinase activity. The products of PI3K-catalysed reactions, phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3), PtdIns(3,4)P2 and PtdIns(3)P, are second messengers in a variety of signal transduction pathways, including those essential to cell proliferation, adhesion, survival, cytoskeletal rearrangement and vesicle trafficking. Here we report the 2.2 A X-ray crystallographic structure of the catalytic subunit of PI3Kgamma, the class I enzyme that is activated by heterotrimeric G-protein betagamma subunits and Ras. PI3Kgamma has a modular organization centred around a helical-domain spine, with C2 and catalytic domains positioned to interact with phospholipid membranes, and a Ras-binding domain placed against the catalytic domain where it could drive allosteric activation of the enzyme.
- Rodriguez-Viciana P, Warne PH, Vanhaesebroeck B, Waterfield MD, Downward J
- Activation of phosphoinositide 3-kinase by interaction with Ras and by point mutation.
- EMBO J. 1996; 15: 2442-51
- Display abstract
- We have reported previously that Ras interacts with the catalytic subunit of phosphoinositide 3-kinase (PI 3-kinase) in a GTP-dependent manner. The affinity of the interaction of Ras-GTP with p85alpha/p110alpha is shown here to be approximately 150 nM. The site of interaction on the p110alpha and beta isoforms of PI 3-kinase lies between amino acid residues 133 and 314. A point mutation in this region, K227E, blocks the GTP-dependent interaction of PI 3-kinase p110alpha with Ras in vitro and the ability of Ras to activate PI 3-kinase in intact cells. In addition, this mutation elevates the basal activity of PI 3-kinase in intact cells, suggesting a direct influence of the Ras binding site on the catalytic activity of PI 3-kinase. Using an in vitro reconstitution assay, it is shown that the interaction of Ras-GTP, but not Ras-GDP, with PI 3-kinase leads to an increase in its enzymatic activity. This stimulation is synergistic with the effect of tyrosine phosphopeptide binding to p85, particularly at suboptimal peptide concentrations. These data show that PI 3-kinase is regulated by a number of mechanisms, and that Ras contributes to the activation of this lipid kinase synergistically with tyrosine kinases.
- Kodaki T, Woscholski R, Hallberg B, Rodriguez-Viciana P, Downward J, Parker PJ
- The activation of phosphatidylinositol 3-kinase by Ras.
- Curr Biol. 1994; 4: 798-806
- Display abstract
- BACKGROUND: Activation of the mammalian phosphatidylinositol 3-kinase complex can play a critical role in transducing growth factor responses. The lipid kinase complex, which is made up of p85 alpha and p110 alpha regulatory and catalytic subunits, becomes associated with a number of activated receptor protein tyrosine kinases, but the mechanism of its activation has not yet been defined. Recent evidence indicates that Ras can bind to the p85 alpha/p110 alpha complex. We describe here the functional regulation of the mammalian phosphatidylinositol 3-kinase complex by Ras. RESULTS: Expression of p110 alpha, the catalytic subunit of phosphatidylinositol 3-kinase, in the fission yeast, Schizosaccharomyces pombe, has been used to demonstrate an inhibitory effect of p85 alpha on p110 alpha activity in intact cells; inhibition did not result from a decrease in p110 alpha expression. In this cellular context, we have investigated the effect of a constitutively active mutant of Ras, v-Ras, either on p85 alpha or p110 alpha-alone, or on the p85 alpha/p110 alpha complex. In the presence of the p85 alpha/p110 alpha complex, v-Ras suppressed cell growth, but an effector-domain mutant of v-Ras did not. The growth-suppressive effect of v-Ras was not seen for any other combination of expressed proteins. The phenotype induced by v-Ras was consistent with activation of the p85 alpha/p110 alpha complex: it was sensitive to the phosphatidylinositol 3-kinase inhibitor, wortmannin, and the cells accumulated 3-phosphorylated polyphosphoinositides. Activation of purified p85 alpha/p110 alpha by purified recombinant Ras in vitro was also demonstrated. CONCLUSIONS: The phosphatidylinositol 3-kinase complex, p85 alpha/p110 alpha, shows a suppressed catalytic function in vivo when compared with free p110 alpha. This complex can, however, be activated by Ras. We suggest that the phosphatidylinositol 3-kinase p85 alpha/p110 alpha complex is a downstream effector of Ras.
- Rodriguez-Viciana P et al.
- Phosphatidylinositol-3-OH kinase as a direct target of Ras.
- Nature. 1994; 370: 527-32
- Display abstract
- Ras (p21ras) interacts directly with the catalytic subunit of phosphatidylinositol-3-OH kinase in a GTP-dependent manner through the Ras effector site. In vivo, dominant negative Ras mutant N17 inhibits growth factor induced production of 3' phosphorylated phosphoinositides in PC12 cells, and transfection of Ras, but not Raf, into COS cells results in a large elevation in the level of these lipids. Therefore Ras can probably regulate phosphatidylinositol-3-OH kinase, providing a point of divergence in signalling pathways downstream of Ras.
Metabolism (metabolic pathways involving proteins which contain this domain)

Structure (3D structures containing this domain)

3D Structures of PI3K_rbd domains in PDB

PDB code	Main view	Title
1e7u		Structure determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin and staurosporine
1e7v		Structure determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin and staurosporine
1e8w		Structure determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin and staurosporine
1e8x		STRUCTURAL INSIGHTS INTO PHOSHOINOSITIDE 3-KINASE ENZYMATIC MECHANISM AND SIGNALLING
1e8y		Structure determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin and staurosporine
1e8z		Structure determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin and staurosporine
1e90		Structure determinants of phosphoinositide 3-kinase inhibition by wortmannin, LY294002, quercetin, myricetin and staurosporine
1he8		Ras G12V - PI 3-kinase gamma complex
2a4z		Crystal Structure of human PI3Kgamma complexed with AS604850
2a5u		Crystal Structure of human PI3Kgamma complexed with AS605240
2chw		A pharmacological map of the PI3-K family defines a role for p110 alpha in signaling: The structure of complex of phosphoinositide 3- kinase gamma with inhibitor PIK-39
2chx		A pharmacological map of the PI3-K family defines a role for p110alpha in signaling: The structure of complex of phosphoinositide 3-kinase gamma with inhibitor PIK-90
2chz		A pharmacological map of the PI3-K family defines a role for p110alpha in signaling: The structure of complex of phosphoinositide 3-kinase gamma with inhibitor PIK-93.
2rd0		Structure of a human p110alpha/p85alpha complex
2v4l		complex of human phosphoinositide 3-kinase catalytic subunit gamma ( p110 gamma) with PIK-284
2wxf		The crystal structure of the murine class IA PI 3-kinase p110delta in complex with PIK-39.
2wxg		The crystal structure of the murine class IA PI 3-kinase p110delta in complex with SW13.
2wxh		The crystal structure of the murine class IA PI 3-kinase p110delta in complex with SW14.
2wxi		The crystal structure of the murine class IA PI 3-kinase p110delta in complex with SW30.
2wxj		The crystal structure of the murine class IA PI 3-kinase p110delta in complex with INK654.
2wxk		The crystal structure of the murine class IA PI 3-kinase p110delta in complex with INK666.
2wxl		The crystal structure of the murine class IA PI 3-kinase p110delta in complex with ZSTK474.
2wxm		The crystal structure of the murine class IA PI 3-kinase p110delta in complex with DL06.
2wxn		The crystal structure of the murine class IA PI 3-kinase p110delta in complex with DL07.
2wxo		The crystal structure of the murine class IA PI 3-kinase p110delta in complex with AS5.
2wxp		The crystal structure of the murine class IA PI 3-kinase p110delta in complex with GDC-0941.
2wxq		The crystal structure of the murine class IA PI 3-kinase p110delta in complex with AS15.
2wxr		The crystal structure of the murine class IA PI 3-kinase p110delta.
2x38		The crystal structure of the murine class IA PI 3-kinase p110delta in complex with IC87114.
2y3a		Crystal structure of p110beta in complex with icSH2 of p85beta and the drug GDC-0941
3apc		Crystal structure of human PI3K-gamma in complex with CH5132799
3apd		Crystal structure of human PI3K-gamma in complex with CH5108134
3apf		Crystal structure of human PI3K-gamma in complex with CH5039699
3csf		Crystal structure of PI3K p110gamma catalytical domain in complex with organoruthenium inhibitor DW2
3cst		Crystal structure of PI3K p110gamma catalytical domain in complex with organoruthenium inhibitor E5E2
3dbs		Structure of PI3K gamma in complex with GDC0941
3dpd		Achieving multi-isoform PI3K inhibition in a series of substituted 3,4-Dihydro-2H-benzo[1,4]oxazines
3ene		Complex of PI3K gamma with an inhibitor
3hhm		Crystal structure of p110alpha H1047R mutant in complex with niSH2 of p85alpha and the drug wortmannin
3hiz		Crystal structure of p110alpha H1047R mutant in complex with niSH2 of p85alpha
3ibe		Crystal Structure of a Pyrazolopyrimidine Inhibitor Bound to PI3 Kinase Gamma
3l08		Structure of Pi3K gamma with a potent inhibitor: GSK2126458
3l13		Crystal Structures of Pan-PI3-Kinase and Dual Pan-PI3-Kinase/mTOR Inhibitors
3l16		Discovery of (thienopyrimidin-2-yl)aminopyrimidines as Potent, Selective, and Orally Available Pan-PI3-Kinase and Dual Pan-PI3-Kinase/mTOR Inhibitors for the Treatment of Cancer
3l17		Discovery of (thienopyrimidin-2-yl)aminopyrimidines as Potent, Selective, and Orally Available Pan-PI3-Kinase and Dual Pan-PI3-Kinase/mTOR Inhibitors for the Treatment of Cancer
3l54		Structure of Pi3K gamma with inhibitor
3lj3		PI3-kinase-gamma with a pyrrolopyridine-benzofuran inhibitor
3mjw		PI3 Kinase gamma with a benzofuranone inhibitor
3ml8		Discovery of the Highly Potent PI3K/mTOR Dual Inhibitor PF-04691502 through Structure Based Drug Design
3ml9		Discovery of the Highly Potent PI3K/mTOR Dual Inhibitor PF-04691502 through Structure Based Drug Design
3nzs		Structure-based Optimization of Pyrazolo -Pyrimidine and -Pyridine Inhibitors of PI3-Kinase
3nzu		Structure-based Optimization of Pyrazolo -Pyrimidine and -Pyridine Inhibitors of PI3-Kinase
3oaw		4-Methylpteridineones as Orally Active and Selective PI3K/mTOR Dual Inhibitors
3p2b		Crystal Structure of PI3K gamma with 3-(2-morpholino-6-(pyridin-3-ylamino)pyrimidin-4-yl)phenol
3pre		Quinazolines with intra-molecular hydrogen bonding scaffold (iMHBS) as PI3K/mTOR dual inhibitors.
3prz		Quinazolines with intra-molecular hydrogen bonding scaffold (iMHBS) as PI3K/mTOR dual inhibitors.
3ps6		Quinazolines with intra-molecular hydrogen bonding scaffold (iMHBS) as PI3K/mTOR dual inhibitors.
3qaq		Crystal structure of PI3K-gamma in complex with triazine-benzimidazole 1
3qar		Crystal structure of PI3K-gamma in complex with triazine-benzimidazole 32
3qjz		Crystal structure of PI3K-gamma in complex with benzothiazole 1
3qk0		Crystal structure of PI3K-gamma in complex with benzothiazole 82
3r7q		Structure-based design of thienobenzoxepin inhibitors of PI3- kinase
3r7r		Structure-based design of thienobenzoxepin inhibitors of PI3-Kinase
3s2a		Crystal structure of PI3K-gamma in complex with a quinoline inhibitor
3sd5		Crystal Structure of PI3K gamma with 5-(2,4-dimorpholinopyrimidin-6-yl)-4-(trifluoromethyl)pyridin-2-amine
3t8m		Rational Design of PI3K-alpha Inhibitors that Exhibit Selectivity Over the PI3K-beta Isoform
3tjp		Crystal Structure of PI3K gamma with N6-(3,4-dimethoxyphenyl)-2-morpholino-[4,5'-bipyrimidine]-2',6-diamine
3tl5		Discovery of GDC-0980: a Potent, Selective, and Orally Available Class I Phosphatidylinositol 3-Kinase (PI3K)/Mammalian Target of Rapamycin (mTOR) Kinase Inhibitor for the Treatment of Cancer
3zim		Discovery of a potent and isoform-selective targeted covalent inhibitor of the lipid kinase PI3Kalpha
3zvv		Fragment Bound to PI3KInase gamma
3zw3		Fragment based discovery of a novel and selective PI3 Kinase inhibitor
4a55		Crystal structure of p110alpha in complex with iSH2 of p85alpha and the inhibitor PIK-108
4ajw		Discovery and Optimization of New Benzimidazole- and Benzoxazole-Pyrimidone Selective PI3KBeta Inhibitors for the Treatment of Phosphatase and TENsin homologue (PTEN)-Deficient Cancers""
4anu		Complexes of PI3Kgamma with isoform selective inhibitors.
4anv		Complexes of PI3Kgamma with isoform selective inhibitors.
4anw		Complexes of PI3Kgamma with isoform selective inhibitors.
4anx		Complexes of PI3Kgamma with isoform selective inhibitors.
4aof		Selective small molecule inhibitor discovered by chemoproteomic assay platform reveals regulation of Th17 cell differentiation by PI3Kgamma
4bfr		Discovery and Optimization of Pyrimidone Indoline Amide PI3Kbeta Inhibitors for the Treatment of Phosphatase and TENsin homologue ( PTEN)-Deficient Cancers
4dk5		Crystal structure of human PI3K-gamma in complex with a pyridyl-triazine inhibitor
4ezj		Potent and Selective Inhibitors of PI3K-delta: Obtaining Isoform Selectivity from the Affinity Pocket and Tryptophan Shelf
4ezk		Potent and Selective Inhibitors of PI3K-delta: Obtaining Isoform Selectivity from the Affinity Pocket and Tryptophan Shelf
4ezl		Potent and Selective Inhibitors of PI3K-delta: Obtaining Isoform Selectivity from the Affinity Pocket and Tryptophan Shelf
4f1s		Crystal structure of human PI3K-gamma in complex with a pyridyl-triazine-sulfonamide inhibitor
4fa6		Design and Synthesis of a Novel Pyrrolidinyl Pyrido Pyrimidinone Derivative as a Potent Inhibitor of PI3Ka and mTOR
4fad		Design and Synthesis of a Novel Pyrrolidinyl Pyrido Pyrimidinone Derivative as a Potent Inhibitor of PI3Ka and mTOR
4fhj		Crystal Structure of PI3K-gamma in Complex with Imidazopyridine 2
4fhk		Crystal Structure of PI3K-gamma in Complex with Imidazopyridazine 19e
4fjy		Crystal structure of PI3K-gamma in complex with quinoline-indoline inhibitor 24f
4fjz		Crystal structure of PI3K-gamma in complex with pyrrolo-pyridine inhibitor 63
4flh		Crystal structure of human PI3K-gamma in complex with AMG511
4ful		PI3 Kinase Gamma bound to a pyrmidine inhibitor
4g11		X-ray structure of PI3K-gamma bound to a 4-(morpholin-4-yl)- (6-oxo-1,6-dihydropyrimidin-2-yl)amide inhibitor
4gb9		Potent and Highly Selective Benzimidazole Inhibitors of PI3K-delta
4hle		Compound 21 (1-alkyl-substituted 1,2,4-triazoles)
4hvb		Catalytic unit of PI3Kg in complex with PI3K/mTOR dual inhibitor PF-04979064
4j6i		Discovery of thiazolobenzoxepin PI3-kinase inhibitors that spare the PI3-kinase beta isoform
4jps		Co-crystal Structures of the Lipid Kinase PI3K alpha with Pan and Isoform Selective Inhibitors
4kz0		Structure of PI3K gamma with Imidazopyridine inhibitors
4kzc		Structure of PI3K gamma with Imidazopyridine inhibitors
4l1b		Crystal Structure of p110alpha complexed with niSH2 of p85alpha
4l23		Crystal Structure of p110alpha complexed with niSH2 of p85alpha and PI-103
4l2y		Crystal Structure of p110alpha complexed with niSH2 of p85alpha and compound 9d
4ovu		4OVU
4ovv		4OVV
4ps3		Structure of PI3K gamma in complex with 1-[6-(5-methoxypyridin-3-yl)-1,3-benzothiazol-2-yl]-3-[2-(1-propyl-1H-imidazol-4-yl)ethyl]urea
4ps7		Structure of PI3K gamma in complex with N-[6-(pyridin-3-yl)-1,3-benzothiazol-2-yl]acetamide
4ps8		Structure of PI3K gamma in complex with N-[6-(5,6-dimethoxypyridin-3-yl)-1,3-benzothiazol-2-yl]acetamide
4tuu		4TUU
4tv3		4TV3
4urk		4URK
4v0i		4V0I
4waf		4WAF
4wwn		4WWN
4wwo		4WWO
4wwp		4WWP
4xe0		4XE0
4xx5		4XX5
4xz4		4XZ4
4ykn		4YKN
4zop		4ZOP
5ae8		5AE8
5ae9		5AE9
5dxh		5DXH
5dxt		5DXT
5dxu		5DXU
5eds		5EDS
5fi4		5FI4
5g2n		5G2N
5g55		5G55
5is5		5IS5
5itd		5ITD
5l72		5L72

Links (links to other resources describing this domain)
INTERPRO IPR000341

PI3K_rbd

Taxonomic distribution of proteins containing PI3K_rbd domain.

3D Structures of PI3K_rbd domains in PDB